The resolution of acute inflammation is an active process temporally orchestrated by local-acting mediators that limit further neutrophil recruitment to sites of inflammation1, 2, 3, 4. During the onset of inflammation, chemical mediators, including the arachidonic acid-derived eicosanoids (e.g. leukotriene (LT) B4 and prostaglandin (PG) E2), mount initiation and propagation of inflammation5, 6, actions that are actively counter-regulated and orchestrated by pro-resolution agonists1, 2, 4. These pro-resolving autacoids also stimulate the clearance of debris, apoptotic cells and bacteria, promoting homeostasis1, 2, 7.
One of the key steps during resolution of inflammation is an increase in local vascular permeability leading to edema6, 8 and the transport of n-3 essential fatty acids (EFA) from blood to the site of inflammation9. n-3 EFA are linked with protective actions in a number of inflammatory conditions including rheumatoid arthritis10, neurological disorders11 and cardiovascular disease12. At the site of inflammation, n-3 EFA are converted to novel potent mediators by exudate leukocytes that promote inflammation-resolution1, 2, 13.
The E-series resolvins, e.g. resolvin (Rv) E1, are produced from 5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid (EPA)14. The D-series resolvins, which include Resolvin D1 (7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid; RvD1) and Resolvin D2 (7S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid; RvD2), the protectins15 and maresins16 are biosynthesized from 4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (DHA). These potent autacoids were initially identified using temporal lipidomics with self-resolving exudates14, 15 and are now appreciated for their ability to stereo-selectively promote inflammation-resolution by tempering leukocyte responses16, 17 13. The resolvins, protectins and maresins are coined specialized pro-resolving mediators (SPM) that by definition limit further neutrophil recruitment to the site of inflammation and promote macrophage clearance of debris, apoptotic cells and bacteria1, 2, 7. In addition, the SPM exert potent actions in promoting wound repair and tissue regeneration as well as dampening inflammatory pain16, 18. Targeted lipid mediator metabololipidomics of tissues obtained from a number of species ranging from primordial organisms such as planaria16 to humans19, 20 indicates that SPM production, including RvD1, RvE119, 20 and maresin 1,2, 14 is evolutionarily conserved.
In mammals, alpha-linolenic acid (9Z,12Z,15Z-octadecatrienoic acid; ALA) is converted via elongation and desaturation to EPA and subsequently to DHA. An intermediate in the conversion of EPA to DHA is n-3 docosapentaenoic acid (7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid; n-3 DPA) 10, 12, 21. n-3 DPA carries 22 carbons and contains five double bonds, with the first double bond being found on carbon 7. The structural differences of n-3 DPA from EPA, DHA and n-6 docosapentaenoic acid (4Z,7Z,10Z,13Z,16Z,-docosapentaenoic acid; n-6 DPA), a biochemically distinct form of DPA where the first double bond is found on carbon 4, are thought to confer unique biophysical properties that are of functional relevance, for example in neuronal systems22. In humans, genome-wide association studies demonstrate that elevation in circulating levels of n-3 DPA and a concomitant decrease in DHA levels are associated with single nucleotide polymorphisms in the gene encoding for the fatty acid elongase 2 (ELOVL2)21. n-3 DPA is present in a number of mammalian tissues including plasma, brain, retina and heart at levels comparable to those of EPA and DHA23. Since circulating levels of n-3 DPA in human cohorts of European, African, Hispanic and Chinese ancestry with mutations in the ELOVL2 gene are elevated21, it remained to be determined whether n-3 DPA is a precursor to novel bioactive molecules.
Therefore, a need exists for a further understanding of, an exploration and/or an identification of new useful materials previously not appreciated as potent biological mediators of interest.